During the past 9 years we established twenty-seven recombinant inbred strains (RIS) from NZB and NZW mice, parents of the Fl females which are the classic model for human systemic lupus erythematosus (SLE). For the first time, recombinational events of the polygenic traits have occurred in some of the RIS that lead to severe, early lupus nephritis (LPN) in females and in some strains also in males. The purpose of this proposal is to insure their continued existence and to characterize these rare and unique lupus-prone strains in order to establish the genetic contributions of NZB and NZW to LPN and autoimmunity in general. RIS have not been considered a promising approach to define the genetic basis of murine SLE, requiring a very large number of lines none of which might recover the full syndrome. This is especially true in the Fl model, since back-crosses have suggested a participation of both H-2 regions. Therefore, it is remarkable that severe early LPN persists in several of our RIS, now at F20-27 of inbreeding; furthermore, the gene(s) susceptible to androgen modulation seems to be differently expressed; males in some lines outlive females, while in others both succumb to early LPN; moreover, some lines do not show severe renal involvement. Regardless of disease pattern, all lines tested to date for H-2 have only NZW markers at K, IA, C4Slp, and D, thus placing the LPN-1 locus of NZB outside of H-2 and suggesting that heterozygosity at H-2 is not required and that the androgen target is not in the S region (C4, C2). Thus, these RIS promise detailed insight into the contribution of the two progenitor strains to LPN development by mapping enzyme and DNA polymorphisms located on at least 7 chromosomes. These studies will make it possible to define the nature of the four previously proposed LPN loci of NZB and NZW. SLE in man is linked to certain HLA markers, but these may not co-vary in lupus families. A definition of LPN-3, in particular, may greatly enhance the understanding of SLE.